This invention relates to novel compounds, to processes for preparing them, and to their use as therapeutic agents.
WO97/48683 (SmithKline Beecham) discloses that benzamide compounds of formula (A) below possess anti-convulsant activity and are therefore believed to be useful in the treatment and/or prevention of anxiety, mania, and related depression disorders. 
where n and p are independently integers from 1 to 4 and (n+p) is from 2 to 5;
R1 is C1-6alkylOxe2x80x94;
R2 is hydrogen, halogen, CN, N3, trifluoromethyldiazirinyl, CF3, CF3Oxe2x80x94, CF3Sxe2x80x94, CF3COxe2x80x94, C1-6alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl-, C1-6alkylOxe2x80x94, C1-6alkylCOxe2x80x94, C3-6cycloalkylCOxe2x80x94, C3-6cycloalkyl-C1-4alkylCOxe2x80x94, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C1-4alkyl-, C1-6alkylSxe2x80x94, C1-6alkylSO2xe2x80x94, (C1-4alkyl), NSO2xe2x80x94 or (C1-4alkyl)NHSO2xe2x80x94;
R3 is hydrogen, halogen, NO2, CN, N3, trifluoromethyldiazirinyl, C1-6 alkylOxe2x80x94, C1-6 alkylSxe2x80x94, C1-6 alkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl-, C1-6alkenyl, C1-6alkynyl, CF3 COxe2x80x94, C1-6alkylCOxe2x80x94, C3-6cycloalkylCOxe2x80x94, C3-6cycloalkyl-C1-4alkylCOxe2x80x94, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C1-4alkyl-, or xe2x80x94NR5R6 where R5 is hydrogen or C1-4 alkyl, and R6 is hydrogen, C1-4alkyl, xe2x80x94CHO, xe2x80x94CO2C1-4alkyl or xe2x80x94COC1-4alkyl;
R4 is hydrogen, C1-6 alkyl, C1-6 alkenyl, or C1-6 alkynyl.
It has now been surprisingly found that tetrahydronaphthyridinyl-carboxamide compounds of formula (I) below possess anti-convulsant activity and are therefore believed to be useful in the treatment and/or prevention of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaemia. Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS).
Accordingly, the present invention provides a compound of formula (I): 
where R1 is hydrogen, C1-6alkyl (optionally substituted by hydroxy or C1-4alkoxy), phenyl-C1-4alkyl-, C1-6alkenyl, or C1-6alkynyl;
R2 is hydrogen or up to three substituents selected from halogen, NO2, CN, N3, CF3Oxe2x80x94, CF3Sxe2x80x94, CF3SO2xe2x80x94, CF3COxe2x80x94, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C1-6perfluoroalkyl, C3-6cycloalkyl, C3-6cycloalkyl-C4alkyl-, C1-6alkylOxe2x80x94, C1-6alkylCOxe2x80x94, C3-6cycloalkylOxe2x80x94, C3-6cycloalkylCOxe2x80x94, C3-6cycloalkyl-C1-4alkylOxe2x80x94, C3-6cycloalkyl-C1-4alkylCOxe2x80x94, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C1-4alkyl-, C1-6alkylSxe2x80x94, C1-6alkylSO2xe2x80x94) (C1-4alkyl)2NSO2xe2x80x94, (C1-4alkyl)NHSO2xe2x80x94, (C1-4alkyl)2NCOxe2x80x94, (C1-4alkyl)NHCOxe2x80x94 or CONH;
or xe2x80x94NR5R6 where R) is hydrogen or C1-4 alkyl, and
R6 is hydrogen, C1-4alkyl, formyl, xe2x80x94COC1-4alkyl or xe2x80x94COC1-4alkyl;
or two R2 groups together form a carbocyclic ring that is saturated or unsaturated, optionally interrupted by O or NH;
R3 groups and R4 groups are each independently hydrogen or C1-6 alkyl and/or the two R3 groups and/or the two R4 groups together form a C3-6 spiroalkyl group, provided that at least one R3 or R4 group is not hydrogen; and
X is selected from hydrogen, halogen, cyano, alkyl and alkoxy.
The compounds of this invention are tetrahydronaphthyridinyl-carboxamides, especially (tetrahydronaphthyridin-3-yl)carboxamides. The carboxamide moiety is typically a benzamide, but when two R2 groups form a carbocyclic ring, this is typically a 5-7 membered ring, and the carboxamide moiety may be a naphthalene carboxamide or an indane carboxamide, or when interrupted by O or NH may be a benzofuran carboxamide or an indole carboxamide.
In the formula (I), alkyl groups, including alkyl groups that are part of other moieties, such as alkoxy or acyl, may be straight chain or branched. Phenyl groups, including phenyl groups that are part of other moieties, in R2 may optionally be substituted with one or more independently selected halogen or C1-6 alkyl. C1-6 alkoxy or C1-6 alkylcarbonyl.
Suitable C3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Suitable halo substituents include fluoro, chloro, iodo and bromo.
It should be appreciated that compounds of the present invention possess chiral centres and as such may exist in different enantiomeric forms, the present invention extends to each enantiomeric form and mixtures thereof including diastereoisomers and racemates.
Preferably, the two R3 groups are the same, and the two R4 groups are the same; typically either both R3 groups are gem-dialkyl or spiro-alkyl, preferably gem-dialkyl, and both R4 groups are hydrogen, or vice versa.
Accordingly one suitable group of compounds is of formula (IA): 
A further suitable group is of formula (IB): 
where R1, R2, R3, R4, X are as defined above.
A suitable group of compounds of formula (I) have
R1 as hydrogen, methyl, ethyl, propyl, benzyl, hydroxyethyl, methoxyethyl,
R2 as hydrogen or one or more of methyl, ethyl, n-butyl, iso-propyl, t-butyl, phenyl, methoxy, ethoxy, iso-propoxy, cyclopropylmethoxy, n-butoxy, phenoxy, benzyloxy, amino, acetylamino, nitro, azido, cyano, bromo, chloro, fluoro, iodo, acetyl, propionyl, pivaloyl, n-butyroyl, iso-butyroyl, benzoyl, iodobenzoyl, trifluoromethyl, perfluoroethyl, trifluoromethoxy, trifluoroacetyl, methanesulfonyl, n-propylsulfonyl, isopropylsulfonyl, dimethylsulfamoyl,
R3 one or both is hydrogen or methyl,
R4 one or both is hydrogen or methyl.
A preferred group of compounds of formula (I) have
R1 as hydrogen, methyl,
R2 as hydrogen or one or more of methyl, ethyl, i-propyl, t-butyl, methoxy, ethoxy, i-propoxy, bromo, chloro, cyano, trifluoromethyl,
R3 both methyl,
R4 both hydrogen.
Examples of compounds of formula (I) are:
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)benzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-iso-propylbenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-ethylbenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-ethoxybenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-chloro-4-iso-propyloxybenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl [1,6]naphthyridin-3-yl)-3-bromo-4-iso-propyloxybenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-acetyl-4-iso-propyloxybenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-ethoxy-3-trifluoromethylbenzamide;
N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-methoxybenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-chloro-4-methoxybenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-methoxybenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-ethylbenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-bromo-4-methylbenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-pivaloylbenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-5-chloro-2-methoxy-4-iso-propyloxybenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-ethoxybenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoroacetylbenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)naphthalene-2-carboxamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-cyano-4-iso-propyloxybenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-acetyl-4-ethylbenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-2,3-dihydrobenzofuran-5-carboxamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-n-butyroyl-4-methoxybenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-n-propionylbenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl-iso-butyroyl-4-methoxybenzamide;
N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethoxy-3-trifluoromethylbenzamide;
N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-acetyl-4-iso-propyloxybenzamide;
N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-methoxybenzamide;
N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6naphthyridin-3-yl)-3-chloro-4-methoxybenzamide;
N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-pentafluoroethyl benzamide;
N-(8,8-dimethyl-5,6,7,8-tetrahydro(1,6]naphthyridin-3-yl)-4-iso-propoxy-3-trifluoromethyl benzamide;
N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethyl-3-trifluoromethyl benzamide;
N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-iso-propyl benzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-chloro-4-ethoxybenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-3-fluoro-4-methoxybenzamide;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-4-methoxy-3-pentafluoroethylbenzamide;
N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-fluoro-4-methoxybenzamide;
N-(8,8-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-propionylbenzamide, and;
N-(5,6,7,8-tetrahydro-6,8,8-trimethyl[1,6]naphthyridin-3-yl)-indole-2-carboxamide.
When synthesised, these compounds are often in salt form, such as the hydrochloride or trifluoroacetate, and such salts also form part of this invention. Such salts may be used in preparing pharmaceutically acceptable salts. The compounds and their salts may be obtained as solvates, such as hydrates, and these also form part of this invention.
The above compounds and pharmaceutically acceptable salts thereof, especially the hydrochloride, and pharmaceutically acceptable solvates, especially hydrates, form a preferred aspect of the present invention.
The administration of such compounds to a mammal may be by way of oral, parenteral, sub-lingual, nasal, rectal, topical or transdermal administration.
An amount effective to treat the disorders hereinbefore described depends on the usual factors such as the nature and severity of the disorders being treated and the weight of the mammal. However, a unit dose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, for example an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20, 30, 40, 50, 100, 200, 300 and 400 mg of the active compound. Unit doses will normally be administered once or more than once per day, for example 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 1 to 1000 mg, for example 1 to 500 mg, that is in the range of approximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, for example 1 to 6 mg/kg/day.
It is greatly preferred that the compound of formula (I) is administered in the form of a unit-dose composition, such as a unit dose oral, including sub-lingual, rectal, topical or parenteral (especially intravenous) composition.
Such compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories. Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disinterants, colorants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art. Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting, agents include sodium lauryl sulphate.
These solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents. Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
For parenteral administration, fluid unit dose forms are prepared containing the compound and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.
Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
Accordingly, the present invention further provides a pharmaceutical composition for use in the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaemia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS) which comprises a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
The present invention also provides a method of treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaemia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS) comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
In a further aspect the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy. Parkinson""s disease, psychosis, migraine, cerebral ischaemia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS).
In a further aspect the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate, thereof as a therapeutic agent, in particular for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson""s disease, psychosis, migraine, cerebral ischaemia, Alzheimer""s disease and other degenerative diseases such as Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Giles de la Tourette""s syndrome), traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, multiple sclerosis (MS) and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction, and amyotrophic lateral sclerosis (ALS).
Another aspect of the invention is a process for the preparation of compounds of formula (I) as herein before described which comprises reacting a compound of formula (II) 
where R1A, R3A, and R4A are R1, R3, and R4 as defined for formula (I) or a group or groups convertible to R1, R3, and R4, and X is as defined for formula (I) with a compound of formula (III) 
where Y is a leaving group such as Cl or OH, and R2A groups are independently R2 as defined for formula (I) or a group or groups convertible to R2, and where required converting an R1A, R2A, R3A, R4A group to a R1, R2, R3, R4 group, converting one R1, R2, R3, R4, X group to another R1, R2, R3, R4, X group, or separating any enantiomers, or converting a salt product to the free base or another pharmaceutically acceptable salt, or converting a free base product to a pharmaceutically acceptable salt.
Conventional conditions for condensation of amines with carboxylic acids or active derivatives thereof, such as acid chlorides, may be used. For example the amides and acids may be reacted in the presence of a mixture of ethyl(dimethylaminopropyl)-carbodiimide/hydroxybenzotriazole in a suitable solvent such as dimethyl formamide, and amines and acid chlorides may be reacted together in a suitable solvent such as ethyl acetate or dichloromethane, optionally in the presence of a base such as triethylamine.
Conversions of an R1A, R2A, R3A, R4A group to a R1, R2, R3, R4 group typically arise when a protecting group is needed during the above coupling reaction or during the preparation of the reactants by the procedures described below. Interconversion of one R1, R2, R3, R4. X group to another typically arises when one compound of formula (I) is used as the immediate precursor of another compound of formula (I) or when it is easier to introduce a more complex or reactive substituent at the end of a synthetic sequence.
Reaction of a compound of formula (III) which is an acid chloride (Y=Cl) typically results in formation of the hydrochloride salt of the compound of formula (I). Hydrochloride salts may also be obtained by passing HCl gas into a solution of the free base product, or adding a solution of HCl in ether.
Compounds of formula (II) may be prepared from a compound of formula (IV): 
by reaction with a dinitro-1-methylpyrid-2-one compound of formula (V): 
in a solution of ammonia in a suitable solvent such as methanol, to obtain a compound of formula (VI) using a procedure similar to that of S. Takada et al. J. Med. Chem, 1996, 39, 2844: 
Compounds of formula (VI) may be converted to compounds of formula (II) by hydrogenation or reduction of the nitro group. For example, a compound of formula (VI) may be hydrogenated by treatment with hydrogen in a suitable solvent such as methanol in the presence of a palladium/carbon catalyst. Alternatively, a compound of formula (VI) may be reduced with stannous chloride in concentrated hydrochloric acid in a suitable solvent such as ethanol.
Compounds of formula (IV) may be prepared using the procedures of Katyalyan et al., Bull. Acad. Sci. USSR (Engl) 1968, 2436.
Compounds of formula (V) may be prepared using the procedure of E. Matsumura. M. Ariga and Y. Tohda. Bull. Chem. Soc. Japan, 52 (8), 2413-2419,(1979).
Compounds of formula (III) may be prepared by further substitution of commercially available benzoic acid derivatives using conventional procedures, or by oxidation of corresponding substituted benzyl alcohols. Alternatively benzoic acids can be prepared from correpondingly substituted phenols, for example by formation of the acetate, coversion to an acetophenone and then to the desired acid.
Where the above described intermediates are novel compounds, they also form part of this invention.
The preparation of compounds of formula (II) is illustrated by the following Descriptions; the preparation of compounds of formula (III) is illustrated by the following Preparations and Procedures: the preparation of compounds of this invention is illustrated by the following Examples. The utility of compounds of this invention is shown by the Pharmacological Data that follow the Examples.